The present invention relates to the process for preparing citalopram, or its salts, and its purification by selective extraction of citalopram or its impurities using organic solvents and water, and the process for preparing citalopram salts.
Citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzo-furanocarbonitryl, is an antidepressant with the following structure: 
Its synthesis from 5-bromophtalide was first described in the U.S. Pat. No. 4,136,193. According to this invention, the last step of citolapram synthesis involves substituting a bromide atom in position 5 of the analogue precursor of citalopram (II) by a cyano group. This substitution is carried out using copper cyanide in dimethylformamide (DMF) in reflux. 
In other publications that appeared later the reaction in which a halogen atom in position 5 of the formula (II) compound is substituted by a cyano group was carried out by reacting with a source of cyanide, for example KCN or NaCN, in the presence of selected catalysts. These processes are shown in the patent applications WO 00/11926 and WO 00/13648.
In patent application WO 00/11926, the cyaniding reaction described uses Ni(0) or Ni(II) catalysts in the presence of catalytic amounts of Cu+ or Zn++ and the reaction is carried out in a solvent, preferably acetonitrile, proprionitrile, tetrahydrofuran (THF) or ethyl acetate.
The patent application WO 00/13648 describes cyaniding by Pd(0) or Pd(II) catalysts such as Pd(PPh3)4, Pd2(dba)3, Pd(PPh)2Cl2, etc., in the presence of catalytic amounts of Cu+ or Zn++ and the reaction is carried out in a solvent, preferably in acetonitrile, proprionitrile, THF, ethyl acetate or DMF.
After completing the cyaniding reaction, crude citalopram is extracted in an organic solvent and is washed several times with water and ethylendiamine or an aqueous solution of ethylendiaminetetraacetic acid (EDTA) in order to eliminate excess cyanide ion and the metals used in this process. Finally, the organic solvent is distilled and crude citalopram substrate is isolated in the form of an oil.
The citalopram prepared by the previously mentioned processs, based on the substitution of a halogen atom in position 5 of the formula (II) compound by a cyano group, has several impurities that must be eliminated before it is transformed into citalopram hydrobromide. The crude citalopram substrate has a purity of approximately 85% as demonstrated in the British patent application GB 2356199.
Some impurities of the citalopram substrate are known. These include the citalopram precursor 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-bromoisobenzofuran [formula (II) compound in which X=Br], the chlorated analogue precursor 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-chloroisobenzofuran [formula (II) compound in which X=Cl], the amide 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-aminocarbonylisobenzofuran [formula (II) compound in which X=CONH2], and other impurities from the autocondensation of the starting material, dimers and polymers (GB 2356199), or from the demethylation [formula (III) compound]. 
It is difficult to purify the citalopram substrate and several processes have been developed with this purpose.
The German patent DE 200007303 discloses purification of citalopram is done by recrystallization in heptane. This process is reported to be useful to eliminate the impurities structurally related with citalopram, especially compounds that differ from citalopram in the substituent in position 5 of the isobenzofuran ring, such as the precursor 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-bromoisobenzofuran [formula (II) compound in which X=Br], the analogous chlorated precursor 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-chloroisobenzofuran [formula (II) compound in which X=Cl] or the amide 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-aminocarbonylisobenzofuran [formula (II) compound in which X=CONH2].
In the British patent GB 2356199, the citalopram substrate is distilled in the presence of sulfolane at a temperature of 200-330xc2x0 C. and a pressure of 0.1-2.0 mm Hg, obtaining distilled citalopram with a purity of approximately 96% determined by HPLC (high pressure liquid chromatography), and indicating that this process is useful to eliminate high molecular weight impurities, dimers and polymers forming during the cyaniding reaction.
In patent application WO 01/45483, citalopram is made to react with a reagent capable of forming an amide group and is later purified to eliminate the amides formed. This mentions that the process could be useful to eliminate the formula (III) compound demethylcitalopram.
The application of all these purification processes requires several stages and special equipment, and new methods must be developed in order to simplify the process used to prepare pure citalopram.
One objective of the present invention is a process for preparing pure citalopram, or one of its salts, that comprises purifying citalopram by selective extractions of citalopram or its impurities using organic solvents and water, under specific conditions of pH and temperature.
An additional objective of this invention concerns a process for preparing citalopram, before its purification, that comprises reacting 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-bromoisobenzofuran with copper cyanide, in the absence of a solvent.
The invention provides a process for preparing pure citalopram, or one of its salts, that comprises purifying citalopram by selective extractions of citalopram or of its impurities with organic solvents and water.
Citalopram can be prepared by any process belonging to the state of the art of the technique. Alternatively, citalopram can be prepared by a process that consists in reacting 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-bromoisobenzofuran of formula 
with copper cyanide in the absence of solvent.
The reaction between this compound 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-bromoisobenzofuran and copper cyanide is conducted at a temperature of between 110xc2x0 C. and 180xc2x0 C. for a period of time ranging from 5 to 15 hours, preferably, at a temperature of between 140xc2x0 C. and 150xc2x0 C., during a period of time between 8 and 9 hours. In these conditions, the formation of high molecular weight impurities, dimers and polymers and also the formation of demethylcitalopram (III) is minimised, and the main impurity of the crude citalopram is the starting material.
When the reaction is complete citalopram is dissolved in an organic solvent immiscible in water, preferably toluene or xylene, and the excess copper cyanide is eliminated by washing in an aqueous medium comprised of water, ethylendiamine, ammonia or an aqueous solution of ethylendiaminetetraacetic acid (EDTA).
In relation to the purification of crude citalopram or one of its salts, it has now been found, surprisingly, that this compound can be purified to a high purity via selective extractions, either of citalopram or of its impurities, with organic solvents and water, under specific conditions of pH and temperature. More specifically, the purification of citalopram according to the present invention is comprised of the following steps:
a) extraction of citalopram dissolved in an organic solvent immiscible in water, with water, at a pH of between 3.0 and 6.0, at a temperature between 10xc2x0 C. and 60xc2x0 C., and separation of the aqueous phase that contains citalopram;
b) washing the phase that contains the citalopram proceeding from step a) with an organic solvent immiscible in water, at a pH between 4.0 and 7.0, at a temperature between 20xc2x0 C. and 60xc2x0 C., and separation of the purified aqueous phase that contains citalopram; and
c) extraction of the citalopram contained in this aqueous phase proceeding from step b) with a solvent immiscible in water at a pH between 5.0 and 7.5, at a temperature between 20xc2x0 C. and 60xc2x0 C.
According to this part of the present invention, the citalopram, dissolved in an organic solvent immiscible in water, is absorbed in water in an acidic medium, for example by the addition of acetic acid, at a pH between 3.0 and 6.0, preferably between 4.8 and 5.4, at a temperature between 10xc2x0 C. and 60xc2x0 C., preferably between 20xc2x0 C. and 50xc2x0 C., after which the aqueous phase containing the citalopram is separated off. The first purification takes place under these conditions and the most apolar impurities remain dissolved in the organic phase.
Next, the aqueous phase (solution) that contains the citalopram is washed with an organic solvent immiscible in water, such as toluene, heptane, hexane, cyclohexane or xylene, at a pH between 4.0 and 7.0, at a temperature between 20xc2x0 C. and 60xc2x0 C., after which the purified aqueous phase that contains the citalopram is separated off. In one specific application, this step b) is carried out with toluene at a pH between 4.0 and 6.0 preferably between 4.8 and 5.0, at a temperature between 20xc2x0 C. and 60xc2x0 C., preferably between 43xc2x0 C. and 47xc2x0 C., or alternatively, with heptane, hexane, cyclohexane or xylene at a pH between 5.0 and 7.0, preferably between 5.8 and 6.3, at a temperature between 20xc2x0 C. and 60xc2x0 C., preferably between 43xc2x0 C. and 47xc2x0 C. In these conditions, the unreacted starting material 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-bromoisobenzofuran, the chlorated impurity 1-[3-(dimethylamine)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-chloroisobenzofuran and residues of apolar impurities not eliminated previously are all eliminated and the citalopram remains in the aqueous phase that is separated off.
Next, the citalopram contained in this aqueous phase proceeding from step b) is extracted with a solvent immiscible in water at a pH between 5.0 and 7.5, at a temperature between 20xc2x0 C. and 60xc2x0 C. In one specific application, this step c) of citalopram extraction is carried out using toluene at a pH of between 5.0 and 7.0, preferably between 5.4 and 5.6, at a temperature between 20xc2x0 C. and 60xc2x0 C., preferably between 43xc2x0 C. and 47xc2x0 C., or, alternatively, with heptane, cyclohexane or xylene at a pH between 5.5 and 7.5, preferably between 6.3 and 6.5, at a temperature between 20xc2x0 C. and 60xc2x0 C., preferably between 43xc2x0 C. and 47xc2x0 C.
The resulting organic extracts that contain citalopram, if desired can be concentrated and the pure citalopram substrate is obtained as an oil with a purity above 99.0% determined by HPLC.
Other organic solvents immiscible in water, such as ethers, esters, halogenated hydrocarbons etc. can be used and the pH and temperature intervals can easily be determined.
Preparing purified citalopram by the process provided by this invention represents an important improvement on the state of the art. Citalopram is manipulated during the whole process in solution until it is transformed into a salt, for example hydrobromide, thus avoiding the tiresome repeated recrystallizations of the citalopram substrate. Similarly, the process can be carried out in conventional laboratories, since it is not necessary to distil the citalopram in special equipment in conditions of high vacuum (0.1-2.0 mmHg) and temperature (240-270xc2x0 C.).
With the process of the invention it is not necessary to submit citalopram to additional reactions to transform some of the impurities into others that are more easy to eliminate. All the impurities are eliminated during the extraction process described.
The purified citalopram substrate can be transformed into a salt, such as one of its own pharmaceutically acceptable salts, for example hydrochloride, hydrobromide, etc. by conventional methods. To do this, in general, the purified citalopram substrate is dissolved in an organic solvent, such as ethyl acetate or isopropanol and a specific amount of the corresponding acid is added. The solution obtained is concentrated or cooled and the salt is isolated by filtration.